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      Novel Findings from CNVs Implicate Inhibitory and Excitatory Signaling Complexes in Schizophrenia

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Summary

          We sought to obtain novel insights into schizophrenia pathogenesis by exploiting the association between the disorder and chromosomal copy number (CNV) burden. We combined data from 5,745 cases and 10,675 controls with other published datasets containing genome-wide CNV data. In this much-enlarged sample of 11,355 cases and 16,416 controls, we show for the first time that case CNVs are enriched for genes involved in GABAergic neurotransmission. Consistent with non-genetic reports of GABAergic deficits in schizophrenia, our findings now show disrupted GABAergic signaling is of direct causal relevance, rather than a secondary effect or due to confounding. Additionally, we independently replicate and greatly extend previous findings of CNV enrichment among genes involved in glutamatergic signaling. Given the strong functional links between the major inhibitory GABAergic and excitatory glutamatergic systems, our findings converge on a broad, coherent set of pathogenic processes, providing firm foundations for studies aimed at dissecting disease mechanisms.

          Highlights

          • First genetic evidence for disruption of GABAergic signaling in schizophrenia
          • No evidence for CNV disruption of biological processes beyond the CNS
          • Support for involvement of NMDAR and ARC complexes in schizophrenia
          • Additional, independent evidence for disruption of glutamatergic signaling

          Abstract

          Pocklington et al. show for the first time that CNVs from individuals with schizophrenia are enriched for genes involved in GABAergic neurotransmission. Previous findings of CNV enrichment among genes involved in glutamatergic signaling are independently replicated and greatly extended.

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          Most cited references 65

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          Gene ontology: tool for the unification of biology. The Gene Ontology Consortium.

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            Biological Insights From 108 Schizophrenia-Associated Genetic Loci

            Summary Schizophrenia is a highly heritable disorder. Genetic risk is conferred by a large number of alleles, including common alleles of small effect that might be detected by genome-wide association studies. Here, we report a multi-stage schizophrenia genome-wide association study of up to 36,989 cases and 113,075 controls. We identify 128 independent associations spanning 108 conservatively defined loci that meet genome-wide significance, 83 of which have not been previously reported. Associations were enriched among genes expressed in brain providing biological plausibility for the findings. Many findings have the potential to provide entirely novel insights into aetiology, but associations at DRD2 and multiple genes involved in glutamatergic neurotransmission highlight molecules of known and potential therapeutic relevance to schizophrenia, and are consistent with leading pathophysiological hypotheses. Independent of genes expressed in brain, associations were enriched among genes expressed in tissues that play important roles in immunity, providing support for the hypothesized link between the immune system and schizophrenia.
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              Neuronal oscillations in cortical networks.

              Clocks tick, bridges and skyscrapers vibrate, neuronal networks oscillate. Are neuronal oscillations an inevitable by-product, similar to bridge vibrations, or an essential part of the brain's design? Mammalian cortical neurons form behavior-dependent oscillating networks of various sizes, which span five orders of magnitude in frequency. These oscillations are phylogenetically preserved, suggesting that they are functionally relevant. Recent findings indicate that network oscillations bias input selection, temporally link neurons into assemblies, and facilitate synaptic plasticity, mechanisms that cooperatively support temporal representation and long-term consolidation of information.
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                Author and article information

                Contributors
                Journal
                Neuron
                Neuron
                Neuron
                Cell Press
                0896-6273
                1097-4199
                03 June 2015
                03 June 2015
                : 86
                : 5
                : 1203-1214
                Affiliations
                [1 ]MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff CF14 4XN, UK
                [2 ]Stanley Center for Psychiatric Research, The Broad Institute of MIT and Harvard, 75 Ames Street, Cambridge, MA 02142, USA
                [3 ]Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115, USA
                Author notes
                []Corresponding author pocklingtonaj@ 123456cardiff.ac.uk
                [∗∗ ]Corresponding author odonovanmc@ 123456cardiff.ac.uk
                [4]

                Current address: Division of Psychiatric Genomics in the Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA

                [5]

                Co-senior author

                S0896-6273(15)00372-4
                10.1016/j.neuron.2015.04.022
                4460187
                26050040
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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                Neurosciences

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